Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
440.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.06 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
not applicable for sensitisation
AF for differences in duration of exposure:
1
Justification:
not applicable for sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
as it comes from human data
AF for other interspecies differences:
1
Justification:
not applicable; human data are used
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
multiple reliable studies with Klimisch code 1 and 2
AF for remaining uncertainties:
1
Justification:
LOAEL to NOAEL (NOAEL/SCL used)
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

There are data available on irritating and sensitisation potential of Benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs., para-, sodium salts (generic name: C20-24 sodium sulfonate). All other data belong to the read-across substances sodium and calcium sulfonates. Since sodium sulfonate target substance is of complex composition that meets the criteria of a UVCB substance, it was decided to derive DNELs also for a residual starting material tetrapropenyl phenol (PDDP, also named as Dodecylphenol, EC 310 -154 -3) which is reproductive toxicant and is, therefore, thought probably to drive toxicity of the C20-24 sodium sulfonate (target substance). The C20-24 sodium sulfonate as manufactured contains 4.9 % PDDP.

DNELs based on the data of read-across substances (without PDDP)

For the C20-24 sodium sulfonate, the following dose descriptors are available without PDDP (Component 1):

Acute/short-term exposure – systemic effects (dermal DNEL):

There are no acute studies available for the test substance. However, there are acute oral studies in rats available for the sodium and calcium sulfonate read-across substances (CAS 7024 -69 -0, Swan, 1972; Analog of CAS 70024-69-0, Sanitised, F., 1989; CAS 68608 -26 -4, Gilman, 1982, Costello, 1983; CAS 115733-09-0 - Sanitised, A., 1981; CAS 61789 -86 -4, Sanitised, E., 1985, Ohees, 1968a, b, Regel, 1970, Gabriel, 1981a; and CAS 68783 -96 -0, overbased version of CAS 61789 -86 -4, Sanitised, C., 1984). The calcium read across substances (Analogue of CAS 70024 -69 -0, CAS 115733-09-0, CAS 68783 -96 -0 and CAS 61789 -86 -4) were also tested in dermal irritation studies in rats or rabbits (Sanitised, G., 1989, Sanitised, B., 1981, Sanitised, J., 1993 and Costello, 1986b). The results show that the read across substances are non-toxic by ingestion and by skin contact; no remarkable systemic toxicity is reported. Oral LD50 values of > 16,000, LD50 > 20,000, LD50 >10,000 - < 20,000 and LD50 > 5,000 mg/kg bw/day were reported.

Since the read across substances are not acutely toxic and this behaviour is also expected for the target substance, no DNEL for acute systemic effects needs to be derived. The DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure.

Acute/short-term exposure – systemic effects (inhalation DNEL):

No acute inhalation study is available for the target substance. However, the sodium sulfonate target substance is not expected to pose an inhalation hazard due to its low vapour pressure (0.0259 Pa at 25 °C). Therefore, no DNEL is required.

Acute/short-term exposure – local effects (dermal DNEL):

The target substance sodium sulfonate is not irritating to the skin of rabbits after 4-hour application of test material (Kern, 1999a). LD50 values above 2,000 were reported for the read across substances in the dermal studies. Thus, the short-term dermal DNEL needs not to be derived and is sufficiently covered by the long-term DNEL for systemic and local effects.

Acute/short-term exposure – local effects (inhalation DNEL):

The magnesium sulfonate target substance does not pose an airborne hazard, due to its low vapour pressure. The long-term inhalation DNEL for systemic effects covers sufficiently local effects.

Long-term exposure – systemic effects (dermal DNEL):

No repeated dose data is available for the target substance. However the long-term systemic DNEL for the dermal route has been derived from the NOAEL of an oral subchronic one-generation reproductive toxicity study in rats with the calcium sulfonate read across substance, (CAS 115733 -09 -0, Bjorn, 2004). A NOAEL of greater than 500 mg/kg bw/day was established. The starting point for the DNEL derivation is the oral NOAEL (route-to-route extrapolation necessary).

Long-term exposure – systemic effects (inhalation DNEL):

There are no dose-response and route-specific information on repeated dose toxicity via inhalation. The target substance does not pose a hazard for humans by the inhalation route of exposure. The inhalation DNEL can be derived from the oral NOAEL of 500 mg/kg bw established in the oral one-generation study in rats with the calcium sulfonate read-across substance (Bjorn, 2004) by route-to-route extrapolation.

Long-term exposure – local effects (dermal DNEL):

The NOAEL as well as the acute local dermal DNEL are calculated as follows: The amount applied to skin is described by 0.2 mL (applied volume) x 0.959 g/mL (density) x 0.1 (= 10 %; NOAEL/SCL concentration) which results in 19.2 mg. The amount applied per unit surface area is described by 19.2 mg (amount applied to skin) / 3.63 cm² skin (based on 3/4" x 3/4" patch noted in a number of studies) resulting in a NOAEL of 5.28 mg/cm². By applying the overall assessment factor of 5, the acute local dermal DNEL amounts to 1.06 mg/cm².

Long-term exposure – local effects (inhalation DNEL):

No long-term inhalation DNEL for local effects is needed since the sodium sulfonate target substance is not expected to be irritating or sensitising to respiratory system. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No-Observed-Effect-Level could be established from the relevant studies. However, any hazard does not exist as no classification of the sodium sulfonate target substance was necessary.

 

Modification of the starting point:

From all available data on the sodium sulfonate target substance (Benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs., para-, sodium salts) and on the sodium and calcium sulfonate read across substances for the different human health endpoints, it is clear that the substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and for the read across substances, reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption):

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation routes available.The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies.

Oral absorption:

Due to the molecular weight of 432.64 -516.79 g/mol, a logPow of 7.99, low water solubility (0.255 mg/L at 20°C) together with the very slight effects found at the highest dose levels in the subacute studies and in the one-generation study in rats with the read-across substances, absorption via the oral route is considered to be slight to moderate for the target substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). The oral absorption is set to 50% since physico-chemical properties of the substance are not in range suggestive of significant absorption from the gastro-intestinal tract. The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

No significant dermal absorption is expected for the sodium sulfonate target substance. The log Pow of 7.99, the water solubility of 0.255 mg/L and the molecular weight of 432.64 - 516.79 g/mol point to a poor absorption through the skin. According to the TGD, Part I, Appendix IV, and ECHA guidance R.7C, 2014, 10% of dermal absorption can be considered in this case, since the criteria for molecular weight and Log Pow are met (MW above 500 g/mol and log Pow > 4). Moreover, a critical assessment of all available data (toxicity effects in the available studies and physicochemical properties) should be taken into account before using default assumptions (ECETOC, TR No. 110). The absorption after dermal exposure is generally more gradual and slower than oral absorption and a lower bioavailability is expected due to the presence of the absorption hindering outer skin layer stratum corneum and a comparatively smaller surface area. Schuhmacher et al. recommended that a low dermal penetration (< 10%) can be assumed for substances with a logPow value >5 or for substances with a Kp value <0.0001 (cm/h). (Schumacher et al., 2003). A skin permeability constant (Kp) of 1.0E-7 cm/min (= 6.0E-6 cm/h) for human epidermis was obtained experimentally for the related substance dodecyl benzenesulfonate (CAS 25155-30-0, Howes, 1975). This substance is structurally similar to the sodium sulfonate target substance, but its alkyl chain consisting of 12 carbon atoms is shorter and therefore it is less lipophilic. The Kp value for the sodium sulfonate target substance, which is even more lipophilic than dodecyl benzenesulfonate, is expected to be much lower. Thus, 10% absorption applies also in this case.

 

Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the sodium sulfonate target substance in humans is available.

 

Reference:

1.      Schuhmacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J.J. (2003). A toolkit for dermal risk assessment: toxicological approach for hazard characterization. Ann. Occup. Hyg., Vol 47 No.8, pp. 641 -652.

 

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.0259 Pa at 25°C) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available and worst-case assumption should be made for route-to-route extrapolation according to ECHA guidance R.8, 2012.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation NOAEC for systemic effects. The following formula was used:
corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used: corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), where ABS is absorption.

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38m³).

Differences in the respiratory volumes between experimental animals and humans were used when a oral rat NOAEL from the subchronic oral one-generation reproductive toxicity study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the subchronic one-generation reproductive toxicity study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the one-generation study was used for the derivation of inhalation long-term DNEL. An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all endpoints and for all exposure routes..

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (subchronic study). However, this is not applicable for skin sensitisation and therefore an assessment factor of 1 was applied.

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied when the NOAEL from the subchronic oral one-generation reproductive toxicity study was used.

 

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL):

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 500 x (50 %/10%) x (10 %/ 10 %) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 5 x 2 x 1 x 1) = 25 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 100.

Long-term exposure - local effects (dermal DNEL)

For the long-term local dermal DNEL, a dermal NOAEL of 5.28 mg/cm² was calculated.

DNEL = 5.28 mg/cm² / (1 x 5 x 1 x 1 x 1) = 1.06 mg/cm².

Assessment factors are: 1 – interspecies, 5 – intraspecies, 1 – study duration (not applicable for sensitisation), 1 – dose response, 1 – quality of data base, 1 - LOAEL = NOAEL. The total AF amounts to 5.

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 500 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 440.79 mg/m³

DNEL = 440.79 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 17.63 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

 

Selected DNELs

DNEL systemic dermal =25 mg/kg bw

DNEL systemic inhalation =17.63 mg/m³

DNEL local dermal (long-term) =1.06 mg/cm²

DNELs based on PDDP

The presence of tetrapropenyl phenol (PDDP) may also contribute to the overall toxicity of the sodium sulfonate target substance. PDDP is classified as a reproductive toxicant (Repr 2), and this component is the driven factor that the target substance was classified as reproductive health hazard. Therefore, the DNELs calculated from either the sodium sulfonate target substance or PDDP were applied to the risk assessment. The results of the exposure assessment covering all relevant exposures show absence of significant human exposure in all scenarios of the manufacture and all identified uses.

For the second component PDDP of the UVCB sodium sulfonate target substance, the following dose descriptors are available (Component 2):

Table. Overview of data and classification status according to CLP guidance

Endpoint

PDDP*

(neat substance)

Result

Classification

Skin irritation

Irritating

Skin Irrit. 2 

Eye irritation

Irritating

Eye Irrit. 2

Skin sens.

Negative

None

Ames

Negative

None

in vitrocytogenicity 

Negative

None

in vitroGene Mutation in mammalian cells

Negative

None

Acute Tox (Oral)

LD50: 2100 mg/kg

None

Acute Tox (Dermal)

LD50: 15,000mg/kg

None

Repeat Dose Tox

28 day oral gavage:

NOAEL: 60 mg/kg/d

None

Repr/Develop Tox

NOAEL: 15 mg/kg/d (two-generation study in rats)

Repr. 2

 

*: Data extracted from REACH registration technical dossier on EC310-154-3/ CAS 121158-58-5 (http://apps. echa. europa. eu/registered/registered-sub).

The DNEL for tetrapropenyl phenol (PDDP) is based on the NOAEL from a two generation reproductive toxicity study with PDDP (the most sensitive endpoint). As the sodium sulfonate target substance as manufactured contains 4.9 % PDDP, a dose of 306.1 mg/kg/day (15 mg/kg bw/day divided by 4.9 %) would be the projected NOAEL since it would deliver no more than 15 mg/kg/day of PDDP. 15 mg/kg/day originates from the two generation study dose regime (http://apps. echa. europa. eu/registered/registered-sub), the linear extrapolation represents the worst case value).

This correction is also used to calculate the inhalation DNEL. The assessment factors used in the calculation of the DNEL are based on the properties of PDDP.

Oral absorption of PDDP is set to 100% based on toxicity effects to reproduction observed in the oral two-generation study in rats.

Justification for 100% dermal absorption for PDDP

Physicochemical properties:

-      MW: <500

-      Measured water solubility: 1. 54 mg/L

-      Measured Log Kow: 7.73

-      Vapour pressure: 1.1 x10-2 Pa at 25°C

Based on discussion on PDDP toxicokinetic (reference: CSR for CAS 121158-58-5, EC 310-154-3), dermal penetration is expected for this substance due to its small molecular weight/size and lipophilicity and 100% dermal absorption was assumed for DNEL derivation. Therefore, same parameters were used in the current communication.

According to ECHA guidance R.8, 2012, worst case inhalation absorption is assumed (100%) for PDDP for oral-to-inhalation extrapolation.

Table. The long-term systemic DNELs for PDDP are calculated as follows (workers)

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 15 mg/kg bw/day

306.1 mg/kg bw/day

 

(concentration in the registered substance is 4.9 %)

Reproductive toxicity

3.06 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 4.9 % to correct for the amount of PDDP to obtain the corrected dose descriptor.

 

An assessment factor of 100 is based on:

4 for allometric scale,

2.5 for remaining difference,

5 for intraspecies difference (workers),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Inhalation

NOAEL: 15 mg/kg bw/day

539.7 mg/m3

Reproductive toxicity

21.6 mg/m3

The NOAEL of 15 mg/kg bw/day is divided by 4.9 % to correct for the amount of PDDP to obtain the corrected dose descriptor.

 

Using a correction factor of 306.1 mg/kg/d (1/sRVrat(0.38) x(ABSoral-rat(100) /ABSinh-human(100)) x(sRVhuman(6.7) /wRV(10))) giving a corrected inhalation NOAEC value of 539.7 mg/m3/d.

 

An assessment factor of 25 is based on

2.5 for interspecies difference (remaining difference),

5 for intraspecies difference (workers),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

No DNEL for skin sensitisation is necessary since PDDP is not a skin sensitiser.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
217.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from an oral one-generation toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0) is available (Bjorn, 2004). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m³/kg/d for a 24-hour exposure and the absorption rates (oral 50 %, inhalation 100 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.528 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
not applicable for sensitisation
AF for differences in duration of exposure:
1
Justification:
not applicable for sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
as it comes from human data
AF for other interspecies differences:
1
Justification:
not applicable; human data are used
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
multiple reliable studies with Klimisch code 1 and 2
AF for remaining uncertainties:
1
Justification:
LOAEL to NOAEL (NOAEL/SCL used)
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable: oral study and oral exposure
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-5 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption):

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert dermal NOAEL into inhalation NOAEC.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNELs for general population (without PDDP)

Long-term exposure - systemic effects (oral):

The oral NOAEL of 500 mg/kg bw had not to be converted.

The oral NOAEL of 500 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 500 mg/kg bw.

DNEL = 500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 2.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default).The total AF amounts to 200.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 12.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 200.

Long-term exposure - local effects (dermal DNEL)

For the long-term local dermal DNEL, a dermal NOAEL of 5.28 mg/cm² was calculated.

DNEL = 5.28 mg/cm² / (1 x 10 x 1 x 1 x 1) = 0.528 mg/cm².

Assessment factors are: 1 – interspecies, 10 – intraspecies, 1 – study duration (not applicable for sensitisation), 1 – dose response, 1 – quality of data base, 1 - LOAEL = NOAEL. The total AF amounts to 10.

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human),where 1.15 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 500 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 217.39 mg/m³

DNEL = 217.39 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 4.35 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 50.

Selected DNELs

DNEL systemic oral =2.5 mg/kg bw

DNEL systemic dermal =12.5 mg/kg bw

DNEL systemic inhalation =4.35 mg/m³

DNEL local dermal (long-term) =0.528 mg/cm²

Calculation of endpoint-specific DNELs for general population (with PDDP)

Similarly as for workers, DNELs are derived for PDDP for systemic effects. No DNEL for skin sensitisation is derived since PDDP is not a skin sensitiser.

Table.The long-term systemic DNELs for PDDP are calculated as follows (general population)

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 15 mg/kg bw/day

306.1 mg/kg bw/day

 

(concentration in the registered substance is 4.9 %)

Reproductive toxicity

1.53 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 4.9 % to correct for the amount of PDDP to obtain the corrected dose descriptor.

 

An assessment factor of 200 is based on:

4 for allometric scale,

2.5 for remaining difference,

10 for intraspecies difference (general population),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Inhalation

NOAEL: 15 mg/kg bw/day

266.2 mg/m3

Reproductive toxicity

5.32 mg/m3

The NOAEL of 15 mg/kg bw/day is divided by 4.9 % to correct for the amount of PDDP to obtain the corrected dose descriptor.

 

Using a correction factor of 306.1 mg/kg/d x (1/sRVrat(1.15) x (ABSoral-rat(100) /ABSinh-human(100))) giving a corrected inhalation NOAEC value of 266.2 mg/m3/d.

 

An assessment factor of 50 is based on

2.5 for interspecies difference (remaining difference),

10 for intraspecies difference (general population),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Oral

NOAEL: 15 mg/kg bw/day

306.1 mg/kg bw/day

 

 

Reproductive toxicity

1.53 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 4.9 % to correct for the amount of PDDP to obtain the corrected dose descriptor.

 

An assessment factor of 200 is based on:

4 for allometric scale,

2.5 for remaining difference,

10 for intraspecies difference (general population),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).